Stroke is a leading cause of disability globally with ischemic stroke accounting for 87% of strokes in the United States. Reperfusion therapies such as thrombolysis and thrombectomy are standard treatments but are limited by time window and access. Argatroban, a selective direct thrombin inhibitor, has been studied to improve neurological outcomes in acute ischemic stroke, but trial results remain conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) as per the PRISMA guidelines that compared the efficacy and safety outcomes of argatroban as an add-on to standard of care (SOC) versus SOC alone for the treatment of AIS.
We publicly preregistered the protocol on July 12, 2024 ( https://osf.io/tygwx/ ). We systematically searched MEDLINE, Embase, and the Cochrane CENTRAL databases from inception through October 2024. Screening, extraction, and risk of bias (RoB 2) were performed independently by 2 reviewers. Included articles were RCTs published in English or French that randomized patients to argatroban with SOC versus SOC alone or placebo. Five articles were included in the systematic review ( Table 1 ). ,,,, Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using random-effects meta-analysis.
Table 1
Study characteristics of randomized studies comparing argatroban with standard of care versus standard of care alone for AIS
| Study | Sample size | Study design | Country | Treatment arms | Inclusion criteria | Maximum follow-up (days) | |
|---|---|---|---|---|---|---|---|
| Intervention | Control | ||||||
| Chen et al. 2023 (ARAIS trial) | 817 | Multicenter | China | Argatroban and standard of care including alteplase | Standard of care including alteplase | Age between 18 and 80 years with AIS at the time of randomization (baseline NIHSS score > 6); and enrolled up to 4.5 hours after the onset of stroke symptoms | 90 |
|
Barreto et al. 2017
(ARTSS-2 trial) |
90 | Multicenter | United States, United Kingdom | Low-dose or high-dose argatroban and standard of care including r-tPA | Standard of care including r-tPA | Age ≥18 years and NIHSS score ≥10 or any NIHSS with proximal intracranial arterial occlusion of terminal internal carotid, M1 or proximal M2, posterior cerebral P1 or proximal P2, distal vertebral, or basilar arteries | 90 |
|
Zhang et al. 2024
(EASE trial) |
628 | Multicenter | China | Argatroban and standard of care | Standard of care | Age ≥18 years with AIS within 48 hours and experienced END with an increase of 2 or more points on the total NIHSS | 90 |
| Liu et al. 2020 | 60 | Multicenter | China | Argatroban and standard of care | Standard of care | Age >40 years, large artery atherosclerosis, acute paraventricular ischemic stroke, acute focal neurological deficit caused by AIS, NIHSS ≥5, and patient treated 4.5 to 48 hours after symptom onset at admission. | 90 |
|
Adeoye et al. 2024
(MOST trial) |
287 | Multicenter | Unites States | Argatroban and standard of care with r-tPA | Placebo with r-tPA | Age ≥18 years with AIS, NIHSS score ≥ 6 prior to r-tPA, treated with r-tPA within 3 hours of stroke onset/time last known well | 90 |
Abbreviations: AIS– acute ischemic stroke; END– early neurological deterioration; NIHSS– National Institutes of Health Stroke Scale; RCT– randomized controlled trial; r-tPA– recombinant tissue plasminogen activator.
Our prespecified primary clinical outcome was an excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days with an overall pooled RR of 1.03 (95% CI: 0.80 to 1.32; I 2: 68%). The secondary outcomes were favorable functional outcome (mRS of 0 to 2) at 90 days, and stroke or other vascular events within 90 days. The favorable functional outcome had a RR of 0.95 (95% CI: 0.81 to 1.11; I 2: 56%). The analysis of stroke and other vascular events was inconclusive due to a wide 95% CI (RR: 0.79; 95% CI: 0.44 to 1.44, I 2: 0%). The safety outcomes included symptomatic intracranial hemorrhage, parenchymal hematoma, and major systemic bleeding within 90 days, as defined by the studies. For symptomatic intracranial hemorrhage and parenchymal hematoma, pooled results were inconclusive with wide CIs with overall pooled RRs respectively 1.13 (95% CI: 0.76 to 1.67, I 2: 0%) and 0.87 (95% CI: 0.52 to 1.45, I 2: 0%) ( Figure 1 ). A meta-analysis could not be conducted for major systemic bleeding as only the ARAIS (Chen et al.) and ARTSS-2 (Barreto et al.) trials reported this outcome. Rates were similar in both trials regardless of intervention.
